Chronic active Epstein-Barr virus disease: molecular pathogenesis, evolving concepts, and emerging therapies

ABSTRACT: Chronic active Epstein-Barr virus (EBV; CAEBV) disease is an uncommon, often lethal T and/or natural killer (T/NK)-cell lymphoproliferative disorder that remains underrecognized outside Asia. Recent advances in molecular and immunopathologic studies, together with the 2022 International Consensus Classification and the fifth World Health Organization lymphoma classification, have consolidated the disease concept and diagnostic framework. Recent studies support a model in which mutated EBV infects hematopoietic stem or lymphoid progenitor cells in the bone marrow, establishing latent infection that persists as these progenitors differentiate into T/NK cells. The infected lymphocytes subsequently undergo clonal expansion, immune evasion, and progressive accumulation of genetic and epigenetic alterations, giving rise to systemic CAEBV disease and, in some cases, transformation into EBV-positive lymphomas or leukemias. We review the clinical spectrum and differential diagnosis in relation to EBV-associated hemophagocytic lymphohistiocytosis and EBV-positive lymphomas or leukemias and highlight geographic differences between Asian and non-Asian cohorts. Despite progress, diagnosis remains hampered by the lack of standardized and commercially available assays to identify infected cell subsets. Hematopoietic stem cell transplantation remains the only curative option; however, transplant-related mortality, relapse, and suboptimal outcomes in adult-onset disease underscore the need for optimized conditioning and pretransplant disease control. We review emerging therapeutic strategies, including programmed cell death 1 blockade, JAK inhibition, and EBV-specific cytotoxic T-lymphocyte therapy, and outline priorities for prospective international trials. This review aims to raise global awareness among hematologists and foster collaborative studies to improve outcomes for patients with CAEBV disease.